3-alkoxymethylenoxy ethers of pregnanes and 19-norpregnanes and their preparation

ABSTRACT

THIS DISCLOSES 3-ALKOXYMETHYLENOXY ETHERS OF THE PREGNANE AND 19-NORPREGNANE SERIES OF STEROIDS WHEREIN THE THE ALKOXY PORTION HAS FROM 1 TO 4 CARBON ATOMS, INCLUSIVE. THE REMAINDER OF THE PREGNANE OR 19-NORPREGNANE STEROID MOLECULE CAN BE SUBSTITUTED AND/OR UNSATURATED AT ONE OR MORE OF POSITIONS C-6,7, C-10, C-16, AND C-17A. THESE COMPOUNDS ARE USEFUL AS PROGESTATIONAL AGENTS. ALSO TAUGHT ARE METHODS USEFUL FOR THE PREPARATION OF THESE COMPOUNDS.

United States Patent Ofice 3,631,032 Patented Dec. 28, 1971 3,631,032 3-ALKOXYMETHYLENOXY ETHERS F PREG- NANES AND 19-NORPREGNANES AND THEIR PREPARATION John H. Fried, Palo Alto, Calif., assignor to Syntex Corporation, Panama, Panama No Drawing. Filed Apr. 16, 1969, Ser. No. 816,828 Int. Cl. C07c 173/00 U.S. Cl. 260-23955 D 14 Claims ABSTRACT OF THE DISCLOSURE This discloses 3-alkoxymethylenoxy ethers of the pregnane and 19-norpregnane series of steroids wherein the the alkoxy portion has from 1 to 4 carbon atoms, inclusive. The remainder of the pregnane or 19-norpregnane steroid molecule can be substituted and/or unsaturated at one or more of positions C-6, 7, 0-10, C-l6, and C17oc. These compounds are useful are progestational agents. Also taught are methods useful for the preparation of these compounds.

The present invention relates to new and useful steroid ethers. It more specifically pertains to novel and useful 3-alkoxymethyleneoxy steroids of the pregnane and 19- norpregnane series, including various molecularly modified derivatives thereof, the steroid nucleus thus bearing at the 03 position a novel group represented by the following Formula A:

ROCH2O wherein R is an alkyl group containing from 1 to 4 carbon atoms, inclusive.

The novel 3-alkoxymethylenoxy ethers in the pregnane and 19-norpregnane series of the present invention are represented by the following Formula I:

R OCHzO in which A is hydrogen or alkyl of up to 8 carbon atoms and B is hydrogen or alkyl or aryl of up to 8 carbon atoms;

R is hydrogen, chloro, fluoro, or methyl;

R is hydrogen or methyl; and

Z is a carbon-carbon single bond or a carbon-carbon double bond or the group CXY in which each of X and Y is hydrogen, chloro, or fiuoro.

In the present specification and claims, the expression alkyl denotes saturated aliphatic hydrocarbon radicals containing the indicated number of carbon atoms and in cluding all isomeric forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. The terms carboxylic acyl and carboxylic acyloxy define acyl and acyloxy groups which are derived from a substituted or unsubstituted carboxylic acid. These acids can be completely saturated or they can possess varying degrees of unsaturation (including aromatic), can be of straight-chain, branched-chain, or cyclic structure, and preferably contain from 1 to 12 carbon atoms. In addition, they can be substituted by functional groups, for example, hydroxy, alkoxy containing up to 6 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino, halogen, and the like. Typical carboxylic acid esters under these definitions thus include acetate, propionate, butyrate, valerate, caproate, enanthate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate, phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylacetate, cyclopentylpropionate, adamantoate, .glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-fi,fl-dimethylglutarate, acetoxyacetate, 2-chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, fl-chloropropionate, trichloroacetate, bicyclo[2.2.2]-octane-l-carboxylate, 4- methylbicyclo[2.2.2]oct-2'-en-l'-carboxylate, and the like.

The compounds of the present invention, as depicted by Formula I above are progestational agents. They are accordingly useful in fertility control, in the treatment of premenstral tension and in lowering blood cholesterol levels. In accordance with these utilities the compounds of the present invention are employed in the same manner as compounds having similar properties such as progesterone, chlormadinone acetate, and so forth. These compounds can be administered via the usual routes, whether orally or parenterally, either singly in conjunction with other medicinal agents, or in pharmaceutically acceptable non-toxic compositions formed by the incorporation of any of of the normally employed excipients.

The compounds of the present invention are prepared by reacting together a 3fi-hydroxy steroid, otherwise corresponding to the compound depicted by Formula I above, and a chloromethyl alkyl ether, wherein the alkyl group contains from 1 to 4 carbon atoms, and a tertiary amine. This reaction is further conducted at temperatures ranging from about 60 C. up to and preferably at the boiling point of the mixture and under reflux and for a period of time sufiicient to complete the reaction. The choice of chloromethyl alkyl ether is made depending upon the final product desired, as depicted by group R. Suitable tertiary amines include the trialkyl amines, such as trimethylamine, triethylamine, tri'butylamine, and so forth, and the cyclic amines such as collidine, pyridine, lutidine and so forth and, generally, those which have a boiling point of at least about 60 C.

The reaction is optionally performed under an atmosphere which is inert to the reactants such as argon and nitrogen. Also, the reaction can optionally be performed under anhydrous or substantially anhydrous conditions. However, while these conditions may under the most favorable circumstances be preferred, they are not an absolute necessity for the practice of the present invention.

In carrying out this reaction, the 3;8-hydroxy starting steroid, chloromethyl alkyl ether, and tertiary amine, are mixed and maintained together in any convenient order or fashion. The reaction mixture is then maintained within the given temperature range for a period of time sufficient to complete the reaction. Upon the completion of the reaction, the reaction mixture is processed via conventional procedures, such as chromatography, decantation, filtration, distillation, evaporation, and so forth to recover and isolate the desired product.

The given reaction consumes the respective reactants in the ratio of one mole of 3fi-hydroxy starting steroid per mole of chloromethyl alkyl ether per mole of tertiary amine. However, the amount of reactants to be employed are not critical, some of the desired product being obtained when employing any proportions thereof. In the preferred embodiments hereof, the tertiary amine is employed in amounts sufficient so as to be useful also as a liquid reaction medium or solvent for the reaction. The chloromethyl alkyl ether is preferably employed in amounts ranging from 3 to 50 moles per mole of starting 3,8-hydroxy starting steroid or in amounts sufiicient so as to be useful also as a co-solvent for the reaction.

The starting 3,8-hydroxy compounds of the present invention are known or can be prepared in accordance with the procedures which are known and standard in the art. Thus, they can "be prepared from the corresponding 3-oxo derivatives by reduction of the oxo group such as with sodium borohydride in methanol or dioxane or with lithium aluminum hydride in tetrahydrofuran or with lithium aluminum-t-butoxide in tetrahydrofuran. Representative starting compounds and processes for the preparation thereof can be found in, for example, US. Pat. 3,338,928.

Representative starting compounds include the following:

pregn-4-ene-3B,l6a,17a-tri0l-20-one, l7tx-heptanoyloxy-19-norpregna-4,6-dien-Bfi-ol-ZO-one, 16a,17a-diacetoxypregn-4-en-3B-ol-20-one. 6-methyl-l6a,l7a-dibenzoyloxy-19-norpregn-4- en-3/8-0l-20-one, 6-fiuoropregna-4,6-diene-3 3,16a,l7a-triol-20-one, and 16a,17a-(2,2-butylidenedioxy)pregn-4-en-3/3-ol-20-one.

The chloromethyl alkyl ether reactants are known compounds and can be prepared in accordance with known methods, vide Wagner and Zook, Synthetic Organic Chemistry, John Wiley and Sons, Inc., New York, 1953 (1963), especially pages 99 and 100 and 226 et seq.

The following examples serve to typify further the manner by which the present invention may be practiced but, as such, should not be construed as limitations upon the overall scope hereof.

EXAMPLE 1 A solution of 200 mg. of 6-chloro-l7a-acetoxypregna- 4,6 diene 3,20 dione in 32 ml. of anhydrous isopropanol and 25 mg. of sodium borohydride is stirred at room temperature for hours. One-hundred ml. of water is added and the resulting suspension extracted several times with ether. The ether phase is dried over sodium sulfate and evaporated to dryness under reduced pressure to yield 6-chloro 17oz acetoxypregna-4,6-dien- 3fl-ol-20-one which may be further purified by recrystallization from ether.

In like matter, the other 3fl-hydroxy compounds, useful as starting materials as herein described, are prepared from the corresponding known 3-oxo derivatives.

EXAMPLE 2 A steroidal solution is prepared by dispersing one gram of 6-chloro 17a acetoxypregna 4,6 dien 3p ol- 20one in 50 ml. of anhydrous collidine at room temperature. To the resulting solution are added 5 ml. of chloromethyl methyl ether portionwise with stirring and at 5 C. under a nitrogen atmosphere. Following the addition, the temperature of the resulting mixture is raised to its boiling point and maintained under reflux for a period of 10 hours. After this time, the reaction mixture is poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate extracts are washed with water and then dried with sodium sulfate. The dried extracts are evaporated to dryness and the residue chromatographed on alumina to obtain the 3/3- methoxymethylenoxy 6 chloro-17a-acetoxypregna-4,6- dien-ZO-one product.

EXAMPLE 3 A solution of 10 grams of 6 chloro 16 methylene- 17a acetoxypregna 4,6 dien 3e ol 20 one dispersed in ml. of anhydrous pyridine is prepared. To this solution is added 200 ml. of chloromethyl ethyl ether. This addition is conducted in a portion-wise manner while maintaining the entire mixture at 5 C. and under a nitrogen atmosphere. The resulting reaction mixture is heated to the boiling point and maintained at reflux temperature, under a nitrogen atmosphere, for 18 hours. After this time, the reaction mixture is poured into water and the aqueous mixture extracted with ethyl acetate. The ethyl acetate extracts, after washing them with water, are dried over anhydrous sodium sulfate and evaporated to dryness. The residue is chromatographed on alumina to provide the 313 ethoxymethylenoxy-6- chloro 16 methylene 17a acetoxypregna 4,6- dien-ZO-one product.

EXAMPLE 4 One gram of 6-chloro-16tx-methyl-17ot-acetoxypregna- 4,6-dien-3ti-ol-20-one is dispersed in 10 ml. of triethylamine at room temperature. To the resulting solution is added 5 grams of chloromethyl n-propyl ether is a portion-Wise fashion with stirring. The reaction mixture is then heated to the boiling point and maintained under reflux for a period of 15 hours. After this time, the reaction mixture is poured into water and the aqueous mixture extracted with several portions of ethyl acetate. The ethyl acetate extracts are washed well with water and then evaporated to dryness. The residue obtained after evaporation is chromatographed on alumina to obtain the 3B-npropoxylmethylenoxy 6 chloro-16ot-methyl-l7a-acetoxypregna-4,6-dien-20-one product.

EXAMPLE 5 The procedure set forth in Example 2 is repeated using 6 chloro 16a,17ot-isopropylidenedioxypregna-4,6-dien- 3fl-ol-20-one, chloromethyl isobutyl ether, and lutidine to obtain the 3B isobutoxymethylenoxy-6-chloro-16a,17aisopropylidencdioxypregna-4,6-dien-20-one product.

EXAMPLE 6 The procedure set forth in Example 3 is repeated using 60:,7a difluoromethylene-6B-chloro-17a-acetoxypregn-4- en-3tiol-20-one and chloromethyl methyl ether to obtain the 3,8-methoxymethylenoxy-6a,7a-difluoromethylene-6/3- chloro-l7a-acetoxypregn-4-en-20-one product.

EXAMPLE 7 To a solution of 10 grams of pregn-4-en-3ti-ol-20-one in 150 ml. of pyridine are added 30 ml. of chloromethyl ethyl ether at 0 C. under a nitrogen atmosphere. The reaction mixture is then heated to and maintained at 70 C. for 12 hours. After this time, it is poured into ice water and extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue oil is chromatographed on washed alumina, eluting with hexanezmethylene chloride (1:1) to obtain the 3p-ethoxymethylenoxypregn-4-en-20-one product In accordance with the foregoing methods, the following are carried out.

By reacting together 6-chloro-17a-acetoxy19-norpregna-4,6-dien-3/3-ol-20-one and chloromethyl methyl ether, there is obtained the 3/3-methoxymethylenoxy-6- chloro-17u-acetoxy-19-norpregna-3,6-dien-20-one product.

By reacting together 6-fluoro-17a-acetoxypregna-4,6- dien-3/3-ol-20-0ne and chloromethyl ethyl ether, there is obtained the 3B-ethoxyrnethylenoxy-6-fiuoro-l7a-acetoxypregna-4,6-dien-20-one product.

By reacting together 6-fluoro-17a-acetoxy-l9-norpregna- 4,6-dien-3B-ol-20-one and chloromethyl n-propyl ether, there is obtained the BB-n-propoxymethylenoxy-6-fiuoro- 17a-acetoxy-19-norpregna-4,6-dien-20-one product.

By reacting together 6-chloro-16-methylene-17a-acetoXy-19-norpregna-4,6-dien-3B-ol-ZO-one and chloromethyl isopropyl ether, there is obtained the 3/8-isopropoxymethylenoxy 6-chloro-l6-methylene-l7a-acetoxy-19-norpregna-4,6-dien-20-one product.

By reacting together 6-fiuoro-16-methylene-l7a-acetoxypregna-4,6-dien-dien-3/3-ol-20-one and chloromethyl nbutyl ether, there is obtained the 3,8-n-butoxymethy1enoxy- 6 fluoro 16-methylene-17u-acetoxypregna-4,6-dien-20- one product.

By reacting together 6-methyl-l6-methylene-17a-acetoXypregna-4,6-dien-3p-ol-20-one and chloromethyl isobutyl ether, there is obtained the 3B-isobutoxymethylenoxy 6 methyl-16-methylene-17a-acetoxypregna-4,6- dien-ZO-one product.

By reacting together 6-chloro-l6u-n1ethyl-17a-acetoxy- 19-norpregna-4,6-dien-3B-ol-20-one and chloromethyl secbutyl ether, there is obtained the 3/3-sec-butoxymethylenoxy 6 chloro-l6a-methyl-17a-acetoxy-19-norpregna- 4,6-dien-20-one product.

By reacting together 6-fil1010-16ot-I116l2hY1-17u-3C61ZOXY- pregna-4,6-dien-3B-ol-20-one and chloromethyl t-butyl ether, there is obtained the 3B-t-butoXymethylenoxy-6- fluoro 16oz methyl-17a-acetoxypregna-4,6-dien-20-one product.

By reacting together 6,l6a-dimethyl-17a-acet0xypregna- 4,6-dien-3fi-ol-20-one and chloromethyl methyl ether, there is obtained the 3B-methoxymethylenoxy-6,16a-dimethyl-l7a-acetoXypregna-4,6-dien-20-one product.

By reacting together 6-chloro-16a,17a-isopropylidenedioxypregna-4,6-dien-3fl-ol-20-one and chloromethyl ethyl ether there is obtained the 3,8-methoxymethylenoxy-6- chloro 16oc,17oc isopropylidenedioxypregna-4,6-dien-20- one product.

By reacting together 60,7a-difiuoromethylene-QS-fiuorol7ix-acetoxypregn-4-en-3B-ol-20-one and chloromethyl npropyl ether, there is obtained the 3,8-n-propoxymethylenoxy 604,70 difluoromethylene-6p-fluoro-17a-acetoxypregn-4-en-20-one product.

By reacting together 60,7a-difluoromethylene-6fi methyl-17a-acetoxypregn-4-en-3 8-ol-20-one and chloromethylisopropyl ether, there is obtained the 3/3-isopropoxymethylenoxy 604,70; difluoromethylene-6/3-methyl-17aacetoxypregn-4-en-20-one product.

By reacting together 16a-chloropregn-4-en-3[3-01-20- one and chloromethyl n-butyl ether, there is obtained the 3B-n butoxymethylenoxy 16or-chloropregn-4-en-20-one product.

By reacting together 16a-fluoropregn-4-ene-3fl,17a-diol- 20-one and chloromethyl isobutyl ether, there is obtained the 3 3 isobutoxymethylenoxy-l6a-fluoropregn-4-en17otol-20-one product.

By reacting pregna-4,6-diene-3,3,16a-diol-20-one and chloromethyl sec-butyl ether, there is obtained the 3,8-secbutoxymethylenoxypregna-4,6-dien-16a-ol-20-one product.

By reacting together 6-methyl-16u-propinoyloxy-19- norpregna-4,6-dien-3fl-ol-20-one and chloromethyl t-butyl ether, there is obtained the 3fl-t-butoxymethylenoxy-6- methyl 16a-propinoyloxy-l9-norpregna-4,6-dien-20-one product.

By reacting together 6,8,7p-methylene-16B-methyl-19- norpregn-4-en-3 8-ol-20-one and chloromethyl methyl ether, there is obtained the 3 8-methoxymethylenoxy-6 3, 7B-methylene-l6 8-methyl-19-norpregn-4-en-20-one product.

By reacting together 613,7,8 dichloromethylene-l7acaproyloxypregn 4 on-3/8-ol-20-one and chloromethyl ethyl ether, there is obtained the 3B-ethoxymethylenoxy- 65,75 dichloromethylene-17ot-caproyloxypregn-4-en-20- one product.

By reacting together 6a,7a-chloromethylene-16-methylene-l9-norpregn-4-en-3,8-ol-20-one and chloromethyl npropyl ether, there is obtained the 3p-n-propoxymethylenoxy-6u,7a-chloromethylene 16 methylene 19 norpregn-4-en-20-one product.

By reacting together 6a,7a fiuoromethylene-6/3-fluoro- 16-Inethylene-17u-acetoXypregn-4-en-3 8-01 20 one and chloromethyl n-butyl ether, there is obtained the 35-11- butoxyrnethylenoXy-6a,7a-dluoromethylene-6fl-fluoro 16- methylene-17a-acetoXypregn-4-en-20-one product.

By reacting together 6a,7a-chlorofluoromethylene-6B- chloro-l6-methylene-17a-acetoXypregn-4en 35 o1 20- one and chloromethyl isobutyl ether, there is obtained the BB-isobutoxymethylenoxy-6a,?a-chlorofluoromethylene-6B-chloro-16-rnethylene-17u-acetoxypregn-4 en 20- one product.

By reacting together 6u,7u.-methylene-16-methylenepregn-4-en-3/3-ol-20-one and chloromethyl sec-butyl ether, there is obtained the 3,B-sec-butoxymethylenoxy-611,7amethylene-l6-methylenepregn-4-en-20-one product.

In addition to the foregoing compounds, there can be obtained the following representative products:

3fl-rnethoxymethylenoxy-6-fiuoro-l6a,l7a-(2,2 pentylidenedioxy)-pregna-4,6-dien-20-one,

3 B ethoxymethylenoxy-16a,17a-(methylphenylmethylenedioxy) -pregn-4-en-20-one,

3fl-propoxymethylenoxy-6-methyl 16a acetoxy 19- norpregnl-en-17a-0l-20-0ne,

3p butoxymethylenoxy-l7a-propionyloxy19-norpregna-4,6-dien-16a-ol-20-one,

3e butoxyrnethylenoxy-65,75-difiuoromethylenepregn- 4-en-17a-ol-20-one,

3(3 rnethoxymethylenoxy-6-chloro-l7m-acetoxypregna- 4,6-dien-20-one,

3B methoxyrnethylenoxy-6-fluoro-17a-acetoxypregna- 4,6-dien-20-one,

3 B-methoxyrnethylenoxy-6-chloro-16 methylene 170cacetoxypregna-4,6-dien-ZO-one,

3fl-methoxymethylenoxy-6-fiuoro-16 methylene 17ozacetoxypregn-4,6-dien-20-one,

3{3-methoxymethylenoxy-6-chloro 16o: methyl 17aacetoxypregna-4,6-dien-20-one,

35 methoxyrnethylenoxy 6 fluoro-16a-methyl-17uacetoxypregna-4,6-dien-20-one,

3fl-methoxymethylenoxy-6-chloro :,170; isopropylidenedioxy-19-norpregna-4,6-dien-20-one,

3,6 methoxymethylenoxy-6-chloro-6,7 difiuoromethylene-17a-acetoxypregn-4-en-20-one, and

3/8 rnethoxymethylenoxy-6-fluoro-6,7-difluoromethylene-17a-acetoxypregn-4-en-20-one.

What is claimed is:

1. The compound represented by the formula wherein R is an alkyl group containing from 1 to 4 carbon atoms, inclusive;

R is hydrogen, hydroxy, or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms;

R is hydrogen, methylene, u-methyl, p-methyl, a-ChlO- r0, a-flLlOfO, a-hydroxy, a-hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms, or when taken together with R the group in which A is hydrogen or alkyl of up to 8 carbon atoms and B is hydrogen or alkyl or aryl of up to 8 carbon atoms;

R is hydrogen, chloro, fiuoro or methyl;

R is hydrogen or methyl; and

Z is a carbon-carbon single bond, a carbon-carbon double bond or the group in which each of X and Y is hydrogen, chloro or fluoro.

2. The compound claimed in claim 1 wherein R is methyl or ethyl.

3. The compound claimed in claim 1 wherein R is hydroxy or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R is hydrogen, methylene, a-methyl, fl-methyl or when taken together with R isopropylidenedioxy; R is chloro, fiuoro or methyl, R is hydrogen or methyl; and Z is a carbon-carbon double bond.

4. The compound claimed in claim 1 wherein R is hydroxy or a hydrocarbon carboxylic acyloxy group of less than 12 carbon atoms; R is hydrogen, methylene, a-methyl, B-methyl or, when taken together with R isopropylidenedioxy; R is chloro or fluoro; R is methyl; and Z is the group 5. The compound claimed in claim 1 wherein R is methyl, R is acetoxy; R is hydrogen; R is chloro; R is methyl; and Z is a carbon-carbon double bond.

6. The compound claimed in claim 1 wherein R is methyl, R is acetoxy; R is hydrogen; R is fluoro; R is methyl; and Z is a carbon-carbon double bond.

7. The compound claimed in claim 1 wherein R is methyl, R is acetoxy; R is methylene; R is chloro; R is methyl; and Z is a carbon-carbon double bond.

8. The compound claimed in claim 1 wherein R is methyl, R is acetoxy; R is methylene; R is fiuoro; R is methyl; and Z is a carbon-carbon double bond.

9. The compound claimed in claim 1 wherein R is methyl, R is acetoxy, R is a-methyl; R is chloro; R is methyl; and Z is a carbon-carbon double bond.

10. The compound claimed in claim 1 wherein R is methyl, R is acetoxy, R is a-methyl; R is fluoro; R is methyl; and Z is a carbon-carbon double bond.

11. The compound claimed in claim 1 wherein R is methyl, R and R taken together is isopropylidenedioxy, R is chloro; R is methyl; and Z is a carbon-carbon double bond.

12. The compound claimed in claim 1 wherein R is methyl, R and R taken together is isopropylidenedioxy, R is chloro; R is hydrogen; and Z is a carbon-carbon double bond.

13. The compound claimed in claim 1 wherein R is methyl, R is acetoxy, R is hydrogen, R is chloro; R is methyl; and Z is the group 14. The compound claimed in claim 1 wherein R is methyl, R is acetoxy, R is hydrogen; R is fiuoro; R is methyl; and Z is the group References Cited UNITED STATES PATENTS 3,033,748 5/ 1962 Wettstein et a1. 16765 3,076,824 2/1963 Harnik 260-3974 3,301,879 1/1967 Wettstein et al 260-3975 HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

, UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 631,032 Dated December 28, 1971 Inventor(s) John H. Fried It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 19, "are" should be as Column 1, line 26, "3-a'lkoxymethyleneoxy" should be 3-alkoxymethylenoxy Column 2, 'line 24, "halogen," should be halogeno, Column 4', line 38, "is" should be in Column 4, line 47, "propoxylmethylenoxy-" should be propoxymethylenoxy-wm Column 5, line 2 1, delete the second occurrence of "dien".

Column 5, line 71, "6- methyl-l60Lpropinoy1oXy-" should be 6methy1l6d-propionyloxy- I Column 5, line 74, "methyl-160Lpropinoyloxy" should be methy1160L-propiony1oxyv v Column 6, line 7, "caproyloxypregri-4-on-3B-o1-20-one" should be caproyloxypregn-4-en-36-01-20-one Signed and sealed this 27th day of June 1972.

(SEAL) Attest:

EDWARD M.FLETCHER,J'R. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM PC4050 USCOMM-DC seam-ps9 Q ,5, GOVERNMENY PRlNTlNG OFFICE 1 I959 0-365-334 

